Dermocosmetic compositions including glycerol-sebacate

ABSTRACT

A method of forming a skin care product includes combining at least one additive including at least one active ingredient with at least one glycerol-sebacate component having repeating units of (glycerol sebacate), water, a co-solvent, and at least one of an emulsifier, a surfactant, and a bodying agent to form the skin care product. A dermocosmetic composition includes at least one additive including at least one active ingredient and at least one glycerol-sebacate component having repeating units of (glycerol sebacate). A method of skin care includes applying a dermocosmetic composition to a skin surface.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/281,516, filed Feb. 21, 2019, which claims priority to and thebenefit of U.S. Provisional Application No. 62/633,380 filed Feb. 21,2018, both of which are hereby incorporated by reference in theirentireties.

FIELD OF THE INVENTION

This application is directed to dermocosmetic compositions. Moreparticularly, the present application is directed to dermocosmeticcompositions including glycerol-sebacate.

BACKGROUND OF THE INVENTION

In many cases, skin is a first line of defense for the human immunesystem and is the largest single and variable organ of the human body.Thus, skin health is an important first line of defense to maintaininggood general health.

Skin condition is associated with a host of effects from disease,therapeutic treatments, such as chemotherapy, trauma, toxic contact orbites, burns, abrasion, compression, vascular conditions, infection,chronic diseases, and necrosis. Skin conditions considered for treatmentby dermocosmetic compositions or care may include, but are not limitedto, acne, photo-aging, natural aging processes, chronic disease comorbidconditions such as, for example, diabetes, couperose, dehydration,rosacea, inflammation, immune-inflammation, auto-immune disorders,irritation, allergic reactions, and environmental exposure.Additionally, immunoinflammatory conditions of the skin and/orgastrointestinal tract for treatment may include, but are not limitedto, psoriasis, scleroderma, Crohn's disease, ulcerative colitis,psoriatic arthritis, and atopic dermatitis.

Dermocosmetic compositions are skin care compositions recommended byhealth care professionals, such as, for example, by a doctor, adermatologist, a pediatrician, an aesthetic physician, or a pharmacist,for specific skincare needs, because their ingredients are safe andeffective with a marginal medicinal effect. As of 2018, the annualdermocosmetic market is about $3 billion (US) and expected to continueto grow based on increases in the aging population, diabetes, skincancer, environmental damage, poor nutrition, and men's care.

Conventional dermocosmetic compositions include at least one activeingredient, where the active ingredient has an effectiveness against aspecific condition documented through rigorous laboratory testing. Thesedermocosmetic compositions are typically distributed through traditionalhealthcare channels, such as pharmacies, over-the-counter (OTC)pharmaceutical drugstores, clinics, medical treatment spas, anddermatologists' offices.

BRIEF DESCRIPTION OF THE INVENTION

It would be desirable to provide a dermocosmetic composition including acarrier or controlled release vehicle that itself is also beneficial tothe skin.

In an embodiment, a method of skin care includes applying adermocosmetic composition to a skin surface. The dermocosmeticcomposition includes at least one additive comprising at least oneactive ingredient and at least one glycerol-sebacate component havingrepeating units of (glycerol sebacate).

In another embodiment, a dermocosmetic composition includes at least oneadditive including at least one active ingredient and at least oneglycerol-sebacate component having repeating units of (glycerolsebacate).

In yet another embodiment, a method of forming a skin care productincludes combining at least one additive including at least one activeingredient with at least one glycerol-sebacate component havingrepeating units of (glycerol sebacate), water, a co-solvent, and atleast one of an emulsifier, a surfactant, and a bodying agent to formthe skin care product.

In another embodiment, a method of skin care includes providing adermocosmetic composition including at least one glycerol-sebacatecomponent having repeating units of (glycerol sebacate). Thedermocosmetic composition has an effective amount of the at least oneglycerol-sebacate component to alter an expression of at least one genein skin after application of the dermocosmetic composition to the skinsurface. The method also includes applying the dermocosmetic compositionto a surface of the skin such that the expression of the at least onegene in the skin is altered by the at least one glycerol-sebacatecomponent.

Various features and advantages of the present invention will beapparent from the following more detailed description, taken inconjunction with the accompanying drawings which illustrate, by way ofexample, the principles of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the effect of poly(glycerol sebacate) (PGS) degradation onhuman Schwann cell proliferation.

FIG. 2 shows protease activity as a function of pH during healing.

FIG. 3 shows the effect of the glycerol:sebacic acid ratio on PGSdegradation rate.

FIG. 4 shows zero-order controlled release of cobalamin from PGS.

FIG. 5 shows PGS microspheres for incorporation into dermocosmeticcompositions in an embodiment of the present disclosure.

FIG. 6 shows a stained cross section of a neo-vessel repaired with aPGS-coated patch.

FIG. 7A shows the total macrophage expression (CD68) for PGS-coated andnon-coated cardiovascular grafts at 1, 3, and 6 months post-implant.

FIG. 7B shows the M1 macrophage expression (CCR7) for PGS-coated andnon-coated cardiovascular grafts at 1, 3, and 6 months post-implant.

FIG. 7C shows the M2 macrophage expression (CD206) for PGS-coated andnon-coated cardiovascular grafts at 1, 3, and 6 months post-implant.

FIG. 8 shows the antimicrobial activity of PGS resin and thermosetagainst five common pathogens relative to a polypropylene (PP) control.

FIG. 9 shows the phase separation distribution of PGS in polyisobutylene(PIB).

FIG. 10 shows weight average molecular weights of glycerol-sebacatecomponents based on gel permeation chromatography (GPC) data for PGSwith seven different glycerol:sebacic acid ratios.

FIG. 11 shows the effect of the presence of a glycerol-sebacatecomponent on gene expression of five genes relative to a controlcomposition.

Wherever possible, the same reference numbers will be used throughoutthe drawings to represent the same parts.

DETAILED DESCRIPTION OF THE INVENTION

Treatment of skin conditions and maintenance of skin health involvebiological mechanisms similar to those found in regenerative medicineand tissue engineering.

In exemplary embodiments, a dermocosmetic composition includes at leastone additive including at least one active ingredient and at least oneglycerol-sebacate component having repeating units of (glycerolsebacate). Depending on the application of the dermocosmeticcomposition, the dermocosmetic composition may further include one ormore additives in addition to the at least one active ingredient.Additional additives may include, but are not limited to, water, aco-solvent, an emulsifier, a surfactant, a bodying agent, and a filler.

As used herein, an active ingredient is any component having aneffectiveness against a specific skin condition documented throughrigorous laboratory testing. The active ingredient provides one or morebenefits to the health of the skin tissue to which the dermocosmeticcomposition is being applied.

Types of active ingredients in a dermocosmetic composition may include,but are not limited to, medicants or active ingredients for specificmedical conditions, antioxidants, biologics for cellular benefit, agentsfor protection against photoaging, analgesics, antibiotics,antimicrobials, pest repellants, skin conditioners, exfoliants,hydration agents, preservatives, antihistamines, cleansing agents,barriers, vitamins, anti-inflammatory agents, small molecules, aminoacids, peptides, proteins, ribonucleic acids (RNAs), deoxyribonucleicacids (DNAs), polysaccharides, proteoglycans, glycosaminoglycans,extracellular matrix (ECM) molecules, or combinations thereof.

More specifically, active ingredients in a dermocosmetic composition mayinclude, but are not limited to, alpha-hydroxy acids, beta-hydroxy acid(salicylic acid), vitamin C (citric acid), curcuminoids, hydroquinone,kojic acid, retinol, L-ascorbic acid, hyaluronic acid, copper peptide,alpha-lipoic acid, niacinamide, ceramides, vitamin E,dimethylaminoethanol (DMAE), dexamethasone, aloe, or combinationsthereof.

The water, when present in the dermocosmetic composition, serves as theprimary solvent to solubilize water-soluble components of thedermocosmetic composition.

The co-solvent, when present in the dermocosmetic composition, aids insolubilizing components with low or no water solubility and may bemiscible or immiscible with water. Appropriate co-solvents may include,but are not limited to, an oxygenated solvent, such as for example, analcohol, a carboxylic acid, an ether, or an ester, an aminated solvent,such as, for example, a primary amine or a secondary amine, a lowmolecular weight solvent with hydrogen bonding capability, a polarsolvent, a non-polar solvent, an ethoxylated low molecular weightsolvent, or combinations thereof.

The emulsifier or surfactant, when present in the dermocosmeticcomposition, aids in compatibilizing the aqueous phase and a non-aqueousphase, when present, to form an emulsion or other similar mixture. Theemulsifier promotes the dispersion of the phase in which it does notdissolve well into the phase in which it dissolves well. Appropriateemulsifiers and/or surfactants may include, but are not limited to,ionic surfactants, non-ionic surfactants, cationic surfactants,amphoteric surfactants, amphiphilic surfactants, or combinationsthereof.

The bodying agent, when present in the dermocosmetic composition,increases the viscosity of, or thickens, the dermocosmetic compositionto give body to the dermocosmetic composition. Appropriate bodyingagents may include, but are not limited to, hydrogels, clays, proteins,cellulosics, or combinations thereof.

The filler, when present in the dermocosmetic composition, improves thephysical properties of the dermocosmetic composition. Appropriatefillers may include, but are not limited to, titanium dioxide, silica,silicates, iron oxides, carbonates, zinc oxides, or combinationsthereof.

Other additives in a dermocosmetic composition may include, but are notlimited to, cholesterol, a small chain fatty acid (SCFA), a glycolicacid, a lactic acid, arbutin, vitamin B, vitamin D, estrogen, anantioxidant, lauric acid, amino acids, magnesium oxide (MgO), decanoicacid, retinoic acid, nicotinamide, B-carotene, resveratrol, naturallight-active compounds, radical-active compounds, or combinationsthereof.

Free glycerol is oily and fugitive as a small molecule, and sebacic acidis solid and requires emulsification and solvency, whereas a preferableglycerol-sebacate component has neither of these disadvantages. Inaddition, the glycerol-sebacate component having repeating units of(glycerol sebacate) may serve as a sustained release polymer, a vehiclecomponent, a therapeutic delivery matrix, or an elastomeric engineeredfilm capable of mimicking the mechanical properties of full thicknessskin. In exemplary embodiments, the glycerol-sebacate component supportscell growth, cell proliferation, cellular health, and molecular health.Specifically, the glycerol-sebacate component may serve as a carrier orvehicle and/or may provide controlled release of one or more of theadditives of the dermocosmetic composition.

The glycerol-sebacate component having repeating units of (glycerolsebacate) may be in the form of poly(glycerol sebacate) (PGS),oligomeric (glycerol sebacate) (OGS), PGS flour, and/or PGSmicrospheres. The PGS may be in resin form or in thermoset form. As usedherein, PGS refers to a polymer of (glycerol sebacate) having a weightaverage molecular weight of greater than 10,000, and OGS refers to anoligomer of (glycerol sebacate) having a weight average molecular weightof 10,000 or less. As used herein, a PGS flour refers to a micronizedthermoset PGS filler that has been processed into a powder of a finepowder size, such as, for example, one having an average particle sizeof less than 1000 micrometers (μm). In addition to molecular weightvariations, glycerol-sebacate components may have stochiometricvariations as well.

The PGS flour may be formed by any method. In some embodiments, the PGSflour is made by a method disclosed in U.S. Patent ApplicationPublication No. 2017/0246316, published on Aug. 31, 2017, and entitled“Composite Containing Poly(glycerol sebacate) Filler”, which is herebyincorporated by reference.

The PGS microspheres may be formed by any method. In some embodiments,the PGS microspheres are made by a method disclosed in U.S. PatentApplication Publication No. 2018/0280912, published on Oct. 4, 2018, andentitled “Cured Biodegradable Microparticles and Scaffolds and Methodsof Making and Using the Same”, which is hereby incorporated byreference.

In some embodiments, the glycerol-sebacate component serves as a basefor additives of the dermocosmetic composition. In other embodiments,the dermocosmetic composition may have a conventional ornon-glycerol-sebacate base, with the glycerol-sebacate component beingincluded to enhance the base composition, such as, for example, in theform of PGS microspheres.

Depending on the type of dermocosmetic composition, theglycerol-sebacate component may be present in an amount anywhere in therange of 1% to 95%, by weight, of the dermocosmetic composition, suchas, for example, 1% to 5%, 5% to 10%, 10% to 20%, 20% to 30%, 30% to40%, 40% to 50%, at least 50%, 50% to 60%, 60% to 70%, 70% to 80%, 80%to 90%, 90% to 95%, or any value, range, or sub-range therebetween.

The dermocosmetic composition may be used to topically apply an activeingredient to the skin, scalp, or hair. Dermocosmetic compositions mayprovide bug protection, environmental protection, germ control, sunprotection, sunburn relief, photo protection, blue light protection,pollution protection, skin protection, cold stress protection, agingprotection, anti-aging, sensory protection, barrier protection,hydration, hair care, skin support, acne treatment, bug-bite treatment,cracked skin treatment, pain relief, infection reduction, acceleratedhealing, skin allergy care, or combinations thereof.

Any method of forming PGS may be used. In some embodiments, theglycerol-sebacate component is made by a method disclosed in U.S. Pat.No. 9,359,472, issued on Jun. 7, 2016, and entitled “Water-MediatedPreparations of Polymeric Materials”, which is hereby incorporated byreference, such as, for example, to provide a component having a lowpolydispersity index, such as, for example, less than 7.5, less than 7,or less than 6.5.

The glycerol-sebacate component may be free or anchored with one or moreadditive. In exemplary embodiments, the glycerol-sebacate component isformed under the following conditions, where R in Reaction 1 may beadditional glycerol-sebacate repeating units crosslinked to the shownglycerol-sebacate repeating units to form a polymer matrix, anotheroligomer or polymer grafted to the shown glycerol-sebacate repeatingunits to form a block co-polymer, or another additive coupled to theshown glycerol-sebacate repeating units:

Additives that are anchorable to the glycerol-sebacate component ormatrix at the above R-location may include, but are not limited to,cholesterol, an SCFA, a glycolic acid (such as in a block-PGS), a lacticacid (such as in a block-PGS), ceramides, hyaluronic acid, arbutin,kojic acid (controlled release), vitamin B, vitamin C, vitamin D,estrogen, an antioxidant, lauric acid, amino acids, MgO, salicylic acid,decanoic acid, retinoic acid, nicotinamide, B-carotene, resveratrol, andnatural light-active and radical-active compounds. Any number ofhydroxyl-bearing and/or carboxyl-bearing groups may be polymerized intothe glycerol-sebacate component by a water-mediated method or othermethods of PGS processing.

In some embodiments, the glycerol-sebacate component is co-polymerized,is in a PGS-block copolymer, or is co-blended. Certain benefits that PGShas in the regenerative medicine and tissue engineering technologies arepreferably conferred to dermocosmetic compositions for skin therapy,healing, regeneration, conditioning, and maintenance of integumenthealth.

Glycerol (glyceryl) esters formed by the glycerol-sebacate component mayinclude, but are not limited to, a glycerol triglyceride of SCFA, aglyceryl acrylate/acrylic acid, a glyceryl arachidonate, a glycerolbehenate, a glyceryl caprylate, a glyceryl dibehenate, a glycerylisostearate, a glyceryl laurate, a glyceryl linoleate, a glycerylisostearate, a glyceryl monostearate, a glycerol oleate, a glycerol paraamino benzoic acid (PABA), a glyceryl polymethylmethacrylate, a glycerolricinolate, a glycerol stearate, a glyceryl stearate citrate, a glycerylstearate lipophilic, a glyceryl tribehenate, a glyceryl triisostearate,a glyceryl trioctenoate, or combinations thereof. The glycerol-sebacatecomponent is preferably not a small molecule but rather a bis-glyceroltriglyceride of a diacid.

In exemplary embodiments, the polymerization of the sebacicdi(carboxylic)acid creates a matrix structure. SCFAs provideantimicrobial activity. These monoacids may be co-polymerized as wellwith sebacic acid (diacid) into the matrix, providing mixed-matrixchemistries.

The unique ability to control the release of both free and anchoredmetabolites as well as grafting components of skin care such as aminoacids, vitamins, and minerals combined with the compatibility withbiopolymers such as collagen and alginate polymers add to the value ofglycerol-sebacate components in dermocosmetic products.

In exemplary embodiments, the dermocosmetic composition further includesone or more additives beneficial to skin care and therapy anchored orblended into the matrix. The one or more additives may be present in anyappropriate amount. Appropriate amounts of additives may include, butare not limited to, anywhere in the range of 0.1% to 90%, by weight, ofthe dermocosmetic composition, such as, for example, 0.1% to 1%, 1% to5%, 5% to 10%, 10% to 20%, 20% to 30%, 30% to 40%, 40% to 50%, 50% to60%, 60% to 70%, 70% to 80%, 80% to 90%, or any value, range, orsub-range therebetween.

The glycerol-sebacate component delivers the components of the polymerand its modifications, including additives that address one or moredermocosmetic issues, to the skin in either a controlled release orcompatibility fashion. In exemplary embodiments, the glycerol-sebacatecomponent efficiently delivers nutrient and/or medicinal components in amanner that does not require over-formulating or extreme use ofadditives for stability and application to achieve results and benefitsfrom certain properties of the glycerol-sebacate component.

In exemplary embodiments, the glycerol-sebacate component selectivelydelivers components and takes advantage of the chemical andbiomechanical properties of the glycerol-sebacate component in skinconditioning as well as films and coatings for protection. In polymerform as a viscoelastic solid, the glycerol-sebacate component is abioresorbable elastomer. The dermocosmetic product may provide healing,regeneration, and/or maintenance to the skin.

PGS has a number of advantageous properties for use in dermocosmeticcompositions. PGS is transparent to ultraviolet (UV) light, allowing fora vehicle that does not compete with UV absorbers. Infrared (IR) andmicrowave (MW) absorption by PGS may be beneficial to skin exposed tolow-frequency electromagnetic (EM) radiation. The ultraviolet-visiblelight (UV-Vis) transparency of PGS supports “blue-light”, IR, and MWprotection. PGS tends to have lipophilic properties but may be modifiedstoichiometrically to be hydrophilic. PGS may serve as a crossovercomponent between tissue engineering and dermocosmetic additives wheretrophic agents and biologic formulation finds favor. PGS may serve as avehicle or compounding agent for vitamins A, D, E, and K because of itslipid-like character. This PGS lipid-like character may aid in deliveryof additive to dermal layers and help protect against cold stressdamage. PGS provides a polymeric amphoteric controlled compatibility forrelease and/or as a formulating base that can hold charged species ofadditives.

The presence of glycerol in the glycerol-sebacate component may providecertain advantages in a dermocosmetic composition. Thepolymeric/oligomeric form of glycerol in a glycerol-sebacate componentmay drastically reduce or eliminate an undesirable “oily” feel and theavoidance of use by people with oily skin to benefit from theanti-inflammatory and barrier recovery features of glycerol. Thepolymeric/oligomeric form of glycerol may aid in the UV protection ofskin, where glycerol-absorber-energy transfer agent-free radicalterminator delivery to the skin chemistry is aided. Thepolymeric/oligomeric form of glycerol may help stabilize components fromfugitive action.

In some embodiments, the glycerol-sebacate component provides a“polymeric” or “oligomeric” form of any skin care additive having theappropriate functionality to react into the glycerol-sebacate matrix orcompound into the formulation for different action in use in addition tothe tissue benefits of the glycerol-sebacate component alone.

The glycerol-sebacate component offers a multi-featured option informulation. The polymeric or oligomeric form of glycerol and sebacicacid provides a vehicle-carrier platform approach, a matrix-entrappedstabilization from fugitive action, and the functional benefit ofcontrolled release of ingredients and delivery or exposure indermocosmetic formulations in immediate and temporal fashion. Theglycerol-sebacate component may be considered as both a compoundingvehicle as well as a platform matrix to react in, anchor, or entraptarget additives for care.

As a surface-eroding system, the biodegradable erosion base of thedermocosmetic formulation is at the glycerol-sebacatecomponent/epidermis interface. This allows the bulk vehicle to alsoprovide bulk barrier “film” or “structured” features to the appliedproduct based on solids, molecular weight, and hydrophobic/hydrophilicbalance.

The glycerol-sebacate component, in an oligomeric or polymeric form ofresin or biodegradable elastomer, can deliver ingredients throughdiffusion and/or surface erosion.

The glycerol-sebacate component, in an oligomeric or polymeric form ofresin or biodegradable elastomer, can deliver ingredients in aspatiotemporal manner.

PGS is a bis-glycerol triglyceride of a diacid polymeric form of a lipidtriglyceride-like structure and may be designed to substitute foranimal-based triglycerides, thereby eliminating allergy, religious, orethnic issues, while providing a base formulating platform for creams,ointments, and salves. The glycerol-sebacate component structure may bedesigned to be an emollient, occlusive, and/or moisturizer.

A PGS platform may be a “carrier” for hydroxyl- or carboxyl-bearingingredients. Using a glycerol-sebacate component as a controlled releasevehicle or additive allows the formulator to modulate the temporal needsof skin care and provide metabolites as part of the functionality andfeature of biodegradability. Preferred embodiments provide aconsumer-friendly ability to apply a dermocosmetic product containing aglycerol-sebacate component as a cream, ointment, salve, or liquid,which may be diluted in aqueous media to spray, coat, sponge, bathe, orhand-deliver the dermocosmetic product. The glycerol-sebacate componentmay be designed to be an effective biodegradable occlusive to optimizemoisture barrier and hydration balance. The glycerol-sebacate componentmay be designed to be used as a polymeric emulsifier/surfactant for oilsand fatty acids. The glycerol-sebacate component may be substituted forpetrolatum, thereby minimizing photoaging by feeding cells as well asbeing biodegradable and occlusive.

In exemplary embodiments, a glycerol-sebacate component provides todermocosmetic compositions all the previously-described benefits toregenerative medicine and tissue engineering with a focus onregeneration and rejuvenation.

A glycerol-sebacate component with application of molecular weightcontrol to the product design is capable of simplifying and stabilizingcomplex formulations and preventing component separation by free energy.For instance, addition of essential amino acids into an aqueous skinconditioner requires the hydrophilic/lipophilic balance (HLB) for thenutrient amino acid to remain uniformly distributed in the compositionthroughout storage and shelf-life. Having components bound or anchoredto the glycerol-sebacate component not only insures a uniformapplication at the time of use but prevents the essential amino acidfrom “falling out” of the distribution, dispersion, emulsion, orsolution. Furthermore, a polymeric or oligomeric version of glycerol andsebacic acid is capable of optimizing the uniform distribution ofglycerol as a humectant and sebacic acid as a pH balancer. Likewise, anycomponent bound to the glycerol-sebacate component temporally anduniformly provides the appropriate delivery as determined by theformulation and application conditions.

In exemplary embodiments, the glycerol-sebacate component provides oneor more of the following attributes to the dermocosmetic composition:endogenous regeneration, bioresorbability, custom controlleddegradation, zero-order release of additives, degradation to metabolitesthrough natural hydrolytic processes, immunomodulation, antimicrobialactivity, elastomeric film conformation,hemocompatibility/non-thrombogenicity, formation of breakdown productsmetabolically favorable to cell proliferation, pro healing action,mechanical tissue compliance, non-irritation, non-cytotoxicity,biocompatibility, non-toxicity, effectiveness in a targeted area for atleast 5 days, biological degradability, non-interference with normalhealing processes, non-interference with immunological functions,applicability in certain settings, including, but not limited to,bleeding, infections, and anastomotic surgery, easyapplication/conformation, compatibility with certain biopolymers,including, but not limited to, collagen, alginates, and ECM materials,such as, for example, proteins, glycoproteins, lipids, and bloodproducts, and processability to create mechanically similarbiodegradable skin-film protection for chronic skin conditions.

In some embodiments, the presence of the glycerol-sebacate componentupregulates or downregulates one or more genes to the benefit ofpromoting healthy skin at or near the application site of thedermocosmetic composition including the glycerol-sebacate component.Such genes may include, but are not limited to, Collagen Type IV Alpha 2(COL₄A₂), which strengthens the ECM, Tissue Inhibitor of MatrixMetalloproteinases 1 (TIMP₁), which degrades matrix metalloproteinase-1(MMP1), Superoxide Dismutase 2, mitochondrial antioxidant manganesesuperoxide dismutase (MnSOD) (SOD₂), which protects against oxidativestress, and Transglutaminase 1 (TGM₁), which is necessary for formationof the cornified cell envelope.

Blue-light skin damage results from prolonged exposure to blue light,with damage-causing emissions peaking at a wavelength of about 440 nm.Certain artificial lighting, flat screen monitors, and computer devicesall emit light at this wavelength, causing chronic damage to the skin.In some embodiments, a dermocosmetic formulation includes aglycerol-sebacate component, beta-carotene, vitamin E, niacin,nicotinamide, salicylic acid, lignin extract, tartrazine, curcumin,and/or turmeric and provides blue light protection. Theglycerol-sebacate component may be free or anchored with one or moreadditive.

Cold stress occurs when skin is exposed to cold temperatures, whichlocally reduces the temperature of the skin below normal bodytemperature. During cold stress, major lipids in the skin, includingfatty acids, ceramides, and cholesterol, are decreased, thus making itmore difficult for epithelial cells to proliferate, thereby affectingthe barrier structure of the skin and its protective role. Cold stressgenerates pro-inflammatory mediators, leading to further tissue damage.In addition, when temperatures decline below normal body temperature,capillary physiology changes, and the penetration resulting fromendothelial cell activity is reduced. PGS is capable of endothelialsupport, and as a polymeric lipid, the glycerol-sebacate component maymitigate cold stress in skin and serve to replenish skin integrity viabreakdown products of the glycerol-sebacate component. In someembodiments, a dermocosmetic formulation includes a glycerol-sebacatecomponent, olive oil, vitamin E, thiamin, riboflavin, niacin,pyridoxine, cobalamin, folic acid, pantothenic acid, biotin,nicotinamide, and/or beeswax and provides cold stress protection. Theglycerol-sebacate component may be free or anchored with one or moreadditive.

Methods of application have been described herein for dermocosmetic usebut a glycerol-sebacate component may similarly be used as a foundationor base for OTC cosmetics, other skin care products, and/or wound careproducts. In some embodiments, the dermocosmetic composition supports awound care treatment, treats a post-chronic condition after the woundcare treatment, or maintains healed skin after the wound care treatment.

Dermal healing and scar formation are greatly impacted by the naturallines of tension in the skin, also known as Langer's lines. All humanshave similar Langer's line patterns, but slight differences existbetween individuals based on their underlying bone structure andanatomy. Langer's lines follow the collagen fiber orientation in thedermis, and they also run parallel to the orientation of underlyingmuscle fibers. During surgery, surgeons prefer to create incisions alongthese lines, if possible, since incisions made parallel to Langer'slines may heal better and produce less scarring than incisions cutacross Langer's lines. Perpendicular incisions tend to pucker and remainmore obvious, and for injuries, this can have an impact on thepresentation of the wound.

In some embodiments, a glycerol-sebacate component in the form of PGS,PGS-alginate, or blends of PGS with other polymers is fabricated into adermal patch for scar reduction. The patch is composed of PGS-basedsheets, films, and/or fibers, and utilizes the elastomeric properties ofPGS to apply directed, controlled compression to the dermal wound.Similar to the z-plasty technique used in cosmetic and orthopedicsurgery and commercial elastomer compressive gels, a patch oriented inthe appropriate direction applies compressive forces to reduce tensionduring wound healing, reducing and relieving scar formation.Specifically, a cause of scar formation is the contracture byfibroblasts on produced collagen I fibers that the cells have depositedas initial granulation tissue. During fibroblast contraction, thenormally disorganized collagen fibers become aligned under thecontraction force, leading to the appearance of a scar. Fibroblasthypertrophy also occurs through mechano-transduction from the tautcollagen fibers, leading to over-production of collagen type I, whichpresents as a bulky scar without hair follicles. Normal wound healing,where scarring does not occur, results in a randomized collagen fiberalignment, which is preferential to achieve normal skin function andappropriate strength. A compressive dermal patch applied to a woundoffsets fibroblast contracture, reduces collagen fiber alignment, andprevents excessive hypertrophy of collagen I, all of which alleviatescar formation.

In some embodiments, the dermal patch including a glycerol-sebacatecomponent may be uniform or may have directionality, applyingcompression in certain axes and tension in other axes. Thedirectionality of the dermal patch depends on the site of applicationwith the knowledge of Langer's lines topography.

In some embodiments, the patch for scar reduction including theglycerol-sebacate component is applied to the wound of a patient byadditive manufacturing, and preferably more specificallythree-dimensional (3D) printing, on-demand based on the geometry and thetopography of the patient's wound. The additively-manufacturedpatient-specific products may be dispensed in a pharmacy or in ahospital. In some embodiments, prior to additive manufacturing of thepatch, the topology of the skin surface is identified, and Langer'slines are mapped onto the skin surface in the area of the wound by 3Dscanning. The boundaries of the wound are identified by imagesegmentation. The wound is then placed in the context of the Langer'slines, and a patch design with fiber geometries that reduce tension isgenerated, prior to additive manufacturing of the patch onto the woundbased on the patch design.

Aside from wound healing, during the aging process, wrinkles in the skinform along these Langer's lines, and some elastomeric films have beencommercialized to smooth out the skin by applying tension that reducesthe visibility of deep lines. In some embodiments, a sheet or patchincluding a glycerol-sebacate component may be used as a topicalproduct, applied daily as a temporary cosmetic enhancement to smooth outthe appearance of wrinkles. The sheet or patch may contain spatial,temporal, and/or formulational elements that are patient-specific, using3D scanning, imaging, or mapping of the individual. 3D printing may beused to fabricate such custom designs.

In some embodiments, a sheet or patch including a glycerol-sebacatecomponent may be used as a facial mask, such as, for example, forhydration, moisturizing, healing, soothing, and/or delivery of activeand/or inactive ingredients. The sheet or patch may contain spatial,temporal, and/or formulational elements that are patient-specific using3D scanning, imaging, or mapping of the individual. 3D printing, inkjetdeposition, and/or laser cutting may be used to fabricate such customdesigns.

In some embodiments, a glycerol-sebacate component may be used incombination with or fabricated into microneedles, such as, for example,to assist in transdermal delivery of active and/or inactive ingredientsacross the keratinocyte barrier, and/or to assist in transdermaldelivery of the glycerol-sebacate itself. This may be especially usefulfor macromolecules, proteins, and other agents that cannot easilypermeate into skin, cannot survive oral ingestion through thegastrointestinal tract, and/or in situations where topical delivery tothe site is advantageous over oral administration. Microneedles may becomposed of, coated with, or used alongside a gel or sheet ofglycerol-sebacate. Microneedles may contain spatial, temporal, andformulational elements that are patient-specific, using 3D scanning,imaging, or mapping of the individual. 3D printing, inkjet deposition,and/or lithography may be used to fabricate such custom designs.

In some embodiments, a dermocosmetic formulation includes aglycerol-sebacate component, vitamin E, thiamin, riboflavin, niacin,pyridoxine, cobalamin, folic acid, pantothenic acid, biotin, and/orsalicylic acid and provides anti-aging. The glycerol-sebacate componentmay be free or anchored with one or more additive.

EXAMPLES

The invention is further described in the context of the followingexamples which are presented by way of illustration, not of limitation.

Example 1

Human Schwann cells were exposed to varying amounts of PGS in tissueculture for 28 days. The cytocompatibility was tested on a neat extractincluding PGS (100%) and dilutions to 50%, 10%, and 1% extracts. Therelative cytocompatibility of each sample was measured at days 7, 14,21, and 28. FIG. 1 shows that the degradation products of PGS alsoincrease cell proliferation in human Schwann cells. Thecytocompatibility was normalized to tissue culture polystyrene (TCPS) inthe absence of PGS. The proliferation of human Schwann cells was foundnot to be negatively impacted by exposure to the degradation products ofPGS over the 28-day period.

Example 2

The curve in FIG. 2 shows the relative protease activity at a woundsite, which varies drastically with the pH at the wound site. FIG. 2illustrates the importance of maintaining a low pH during the earlyphases of healing to minimize protease activity, which can be“non-healing” if left uncontrolled at a neutral or basic pH. Thepresence of sebacic acid at the wound site, as a consequence ofdegradation of the glycerol-sebacate component, lowers the pH, which mayhelp modulate the wound site and/or skin pH for an ideal healingenvironment.

Example 3

PGS resin samples were polymerized from three different glycerol:sebacicacid mole ratios, 0.7:1, 1:1, and 1.3:1, under otherwise identicalwater-mediated conditions. Thermoset versions of the PGS samples wereplaced in water, and the degradation of the samples was measured as apercentage of mass loss over a 90-day period. FIG. 3 shows that whileall three samples degraded linearly from day 7 up to day 90, indicatingsurface degradation, the degradation rate increased with increasingglycerol:sebacic acid mole ratio, as seen by comparing the 0.7:1 ratioline 40 to the 1:1 ratio line 42 and the 1:1.3 ratio line 44.

Example 4

Three different samples of cobalamin (vitamin B12)-loaded PGS wereprepared and tested for release of the vitamin B12 in an aqueousenvironment. In one sample, PGS resin was loaded with 1% vitamin B12, byweight, and cured for 48 hours to form a 1 mm PGS thermoset film. In asecond sample, PGS resin was loaded with 3% vitamin B12, by weight, andcured for 48 hours to form a 1 mm PGS thermoset film. In a third sample,PGS resin was loaded with 3% vitamin B12, by weight, and applied as athin film to a textile made of polyethylene terephthalate (PET). FIG. 4shows the measured zero-order controlled release of vitamin B12 fromPGS. The 3% loading 50 provided a slightly higher relative release ratethan the 1% loading 52. The coating 54 released vitamin B12 at asignificantly lower relative rate than either of the other two samples.Zero-order controlled release from PGS has also been observed forvitamin E and curcumin.

Example 5

FIG. 5 shows PGS formed into microspheres for incorporation intodermocosmetic compositions. The PGS microspheres may be unloaded orloaded with one or more additives. The particle size may be tuned, forexample, by adjusting the intensity of shear mixing by adjusting thenumber of revolutions per minute (RPM), the impeller size and/or shape,and/or the size and shape of the reaction vessel, by adjusting thecontinuous phase:dispersed phase ratio, by adjusting the viscosity ofthe continuous phase, by adjusting the viscosity of the dispersed phase,and/or by the absence or presence and amount of emulsifiers and/orstabilizers.

Example 6

A polyglycolic acid (PGA) cardiovascular patch was coated with PGS andimplanted into a defect made in the carotid artery of a sheep. Thecarotid defect and surrounding tissue were harvested at three months andprocessed for histopathological analysis. FIG. 6 shows a representativecross-section through the distal portion of the PGS-coated PGAcardiovascular patch. The area of the patch placement with the presenceof an endothelial layer and the absence of graft material in a repairedarea is indicated by a dashed line. Uniform reconstruction of thevascular wall by a fibro-muscular tissue is indicated by a bracket andarrowheads. The image indicates an endothelialized lumen with noevidence of vascular occlusion, such as, for example, via neointimalgrowth or thrombosis. No evidence of adverse pathology, such as, forexample, exuberant inflammation and/or necrosis, was observed. Thisresult suggests that PGS encourages vascular reconstruction andendothelial proliferation in neo-vessels, as may be needed in dermalcapillary beds.

Example 7

PGS-coated and uncoated cardiovascular grafts were implanted and thentested for macrophage expression post-implant. The grafts were implantedas infrarenal abdominal aorta inter-positional grafts in a rat forperiods of one, three, and six months. FIG. 7A shows the totalmacrophage expression (CD68) on PGS-coated (solid bar) and non-coated(checkered bar) cardiovascular grafts at one, three, and six monthspost-implant. FIG. 7B shows the M1 macrophage expression (CCR7) onPGS-coated and non-coated cardiovascular grafts at one, three, and sixmonths post-implant. FIG. 7C shows the M2 macrophage expression (CD206)on PGS-coated and non-coated cardiovascular grafts at one, three, andsix months post-implant. Total macrophage expression is lower and M2expression is elevated at 3 months in the PGS-coated grafts relative tothe uncoated grafts.

Example 8

The antimicrobial activity of PGS in both resin and thermoset forms wastested against five common pathogens, methicillin-resistantStaphylococcus aureus (MRSA), Staphylococcus epidermidis, Pseudomonasaeruginosa, methicillin-resistant Staphylococcus epidermidis (MRSE), andCandida albicans using the JIS Z2801 method (ISO 22196). FIG. 8 showsmeasured microbial colony forming unit (CFU) counts after 24 hoursrelative to a polypropylene (PP) control. PGS in both resin andthermoset forms showed strong antimicrobial activity against all fivepathogens.

Example 9

FIG. 9 shows the phase separation distribution of PGS resin andpolyisobutylene (PM) resin in a 50:50 w/w mixture, indicating a deliverymethod or formulation option for skin care and use. The image in FIG. 9was obtained by a laser-directed infrared (LDIR) microscope (AgilentTechnologies, Santa Clara, Calif.). The lighter areas in FIG. 9represent the PGS, whereas the darker areas represent the PM.

Example 10

Glycerol-sebacate components were formed with ratios of glycerol tosebacate of 0.7:1, 0.8:1.0, 0.9:1.0, 1.0:1.0, 1.1:1.0, 1.2:1.0, and1.3:1.0. The resulting compositions were tested for molecular weight byGPC, for hydrophilicity/hydrophobicity, and for viscosity. FIG. 10 showsthat stoichiometric variation of the polymerization process affords theability to control the molecular weight of the resulting PGS polymer.Stoichiometric variations may also be used to vary the properties of theglycerol-sebacate component from hydrophilic (1.3:1.0 ratio) to neutral(1.0:1.0 ratio) to hydrophobic (0.7:1.0 ratio) and from high viscosity(0.7:1.0 ratio) to low viscosity (1.3:1.0 ratio).

Example 11

A genetic study was conducted to understand how gene expression in theskin is influenced by the presence of PGS. The study was performed usinga full-thickness in vitro skin culture model containing epidermal anddermal cell layers (EFT-400, MatTek Corp., Ashland, Mass.). Geneexpression was assessed in the full-thickness tissues following either24-hour or 72-hour exposure to PGS. The following treatment groups wereincluded in the study (N=4): 1) PGS (10% w/w in DMSO), 2) PGS (50% w/win DMSO), 3) vehicle control [DMSO], and 4) untreated control. Geneexpression was analyzed using a Standard Skin Panel (Genemarkers, LLC,Kalamazoo, Mich.), a qPCR-based gene expression panel that contains 107target genes and 5 endogenous control genes. FIG. 11 shows that the geneexpressions for COL₄A₂, TIMP₁, MMP1, SOD₂, and TGM₁ were all affected byuse of PGS on a full-thickness in vitro skin culture model containingepidermal and dermal cell layers.

While the invention has been described with reference to one or moreexemplary embodiments, it will be understood by those skilled in the artthat various changes may be made and equivalents may be substituted forelements thereof without departing from the scope of the invention. Inaddition, many modifications may be made to adapt a particular situationor material to the teachings of the invention without departing from theessential scope thereof. Therefore, it is intended that the inventionnot be limited to the particular embodiment disclosed as the best modecontemplated for carrying out this invention, but that the inventionwill include all embodiments falling within the scope of the appendedclaims. In addition, all numerical values identified in the detaileddescription shall be interpreted as though the precise and approximatevalues are both expressly identified.

What is claimed is:
 1. A method of skin care comprising: applying adermocosmetic composition to a skin surface, the dermocosmeticcomposition comprising: at least one additive comprising at least oneactive ingredient; and at least one glycerol-sebacate component havingrepeating units of (glycerol sebacate).
 2. The method of claim 1,wherein the at least one additive is selected from the group consistingof cholesterol, a small chain fatty acid, a glycolic acid, a lacticacid, arbutin, vitamin B, vitamin D, estrogen, an antioxidant, lauricacid, an amino acid, magnesium oxide, decanoic acid, retinoic acid,nicotinamide, B-carotene, resveratrol, a natural light-active compound,a radical-active compound, and combinations thereof.
 3. The method ofclaim 1, wherein the at least one active ingredient is selected from thegroup consisting of an alpha-hydroxy acid, a beta-hydroxy acid,salicylic acid, citric acid, a curcuminoid, hydroquinone, kojic acid,retinol, L-ascorbic acid, hyaluronic acid, copper peptide, alpha-lipoicacid, niacinamide, a ceramide, a peptide, vitamin E,dimethylaminoethanol, and combinations thereof.
 4. The method of claim1, wherein the at least one glycerol-sebacate component is selected fromthe group consisting of poly(glycerol sebacate), oligomeric (glycerolsebacate), and thermoset poly(glycerol sebacate) flour.
 5. The method ofclaim 1, wherein the dermocosmetic composition further comprises water,a co-solvent, and a component selected from the group consisting of anemulsifier, a surfactant, a bodying agent, and combinations thereof. 6.The method of claim 1, wherein the at least one glycerol-sebacatecomponent is applied for the purpose of altering an expression of atleast one gene in skin after application of the dermocosmeticcomposition to the skin surface.
 7. A dermocosmetic compositioncomprising: at least one additive comprising at least one activeingredient; and at least one glycerol-sebacate component havingrepeating units of (glycerol sebacate).
 8. The dermocosmetic compositionof claim 7, wherein the at least one additive is covalently attached tothe at least one glycerol-sebacate component.
 9. The dermocosmeticcomposition of claim 7, wherein the at least one additive is selectedfrom the group consisting of cholesterol, a small chain fatty acid, aglycolic acid, a lactic acid, arbutin, vitamin B, vitamin D, estrogen,an antioxidant, lauric acid, an amino acid, magnesium oxide, decanoicacid, retinoic acid, nicotinamide, B-carotene, resveratrol, a naturallight-active compound, a radical-active compound, and combinationsthereof.
 10. The dermocosmetic composition of claim 7, wherein the atleast one active ingredient is selected from the group consisting of analpha-hydroxy acid, a beta-hydroxy acid, salicylic acid, citric acid, acurcuminoid, hydroquinone, kojic acid, retinol, L-ascorbic acid,hyaluronic acid, copper peptide, alpha-lipoic acid, niacinamide, aceramide, a peptide, vitamin E, dimethylaminoethanol, and combinationsthereof.
 11. The dermocosmetic composition of claim 7, wherein the atleast one glycerol-sebacate component is selected from the groupconsisting of poly(glycerol sebacate), oligomeric (glycerol sebacate),and thermoset poly(glycerol sebacate) flour.
 12. The dermocosmeticcomposition of claim 7 further comprising water, a co-solvent, and acomponent selected from the group consisting of an emulsifier, asurfactant, a bodying agent, and combinations thereof.
 13. Thedermocosmetic composition of claim 7, wherein the at least oneglycerol-sebacate component forms a matrix of the dermocosmeticcomposition.
 14. A method of forming a skin care product comprising:combining at least one additive comprising at least one activeingredient with at least one glycerol-sebacate component havingrepeating units of (glycerol sebacate), water, a co-solvent, and acomponent selected from the group consisting of an emulsifier, asurfactant, a bodying agent, and combinations thereof.
 15. The method ofclaim 14, wherein the combining further comprises covalently attachingthe at least one additive to the at least one glycerol-sebacatecomponent.
 16. The method of claim 14, wherein the at least one additiveis selected from the group consisting of cholesterol, a small chainfatty acid, a glycolic acid, a lactic acid, arbutin, vitamin B, vitaminD, estrogen, an antioxidant, lauric acid, an amino acid, magnesiumoxide, decanoic acid, retinoic acid, nicotinamide, B-carotene,resveratrol, a natural light-active compound, a radical-active compound,and combinations thereof.
 17. The method of claim 14, wherein the atleast one active ingredient is selected from the group consisting of analpha-hydroxy acid, a beta-hydroxy acid, salicylic acid, citric acid, acurcuminoid, hydroquinone, kojic acid, retinol, L-ascorbic acid,hyaluronic acid, copper peptide, alpha-lipoic acid, niacinamide, aceramide, a peptide, vitamin E, dimethylaminoethanol, and combinationsthereof.
 18. The method of claim 14, wherein the at least oneglycerol-sebacate component is selected from the group consisting ofpoly(glycerol sebacate), oligomeric (glycerol sebacate), and thermosetpoly(glycerol sebacate) flour.
 19. The method of claim 14, wherein thedermocosmetic composition further comprises water, a co-solvent, and acomponent selected from the group consisting of an emulsifier, asurfactant, a bodying agent, and combinations thereof.
 20. A method ofskin care comprising: providing a dermocosmetic composition comprisingat least one glycerol-sebacate component having repeating units of(glycerol sebacate), the dermocosmetic composition having an effectiveamount of the at least one glycerol-sebacate component to alter anexpression of at least one gene in skin after application of thedermocosmetic composition to the skin surface; and applying thedermocosmetic composition to a surface of the skin such that theexpression of the at least one gene in the skin is altered by the atleast one glycerol-sebacate component.